tbuckley/cabot-search huggingface dataset:
The regulation of insulin receptor/insulin-like growth factor 1 receptor ratio, an important factor for breast cancer prognosis, by TRIP-Br1
Authors: Thi Ngoc Quynh Nguyen, Samil Jung, Hai Anh Nguyen, BeomSuk Lee, Son Hai Vu, Davaajargal Myagmarjav, Hye Hyeon Eum, Hae-Ock Lee, Taeyeon Jo, Yeongseon Choi, Myeong-Sok Lee
Journal: Journal of Hematology & Oncology (2022)

Abstract Much higher risk of cancer has been found in diabetes patients. Insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) have been extensively studied in both breast cancer and diabetes therapies. Interestingly, a recent study proposed that IR/IGF1R ratio is an important factor for breast cancer prognosis. Women with higher IR/IGF1R ratio showed poor breast cancer prognosis as well as hyperinsulinemia. Here, we propose a novel mechanism that oncogenic protein TRIP-Br1 renders breast cancer cells and insulin deficient mice to have higher IR/IGF1R ratio by positively and negatively regulating IR and IGF1R expression at the protein level, respectively. TRIP-Br1 repressed IR degradation by suppressing its ubiquitination. Meanwhile, TRIP-Br1 directly interacts with both IGF1R and NEDD4-1 E3 ubiquitin ligase, in which TRIP-Br1/NEDD4-1 degrades IGF1R via ubiquitin/proteasome system. TRIP-Br1-mediated higher IR/IGF1R ratio enhanced the proliferation and survival of breast cancer cells. In conclusion, current study may provide an important information in the regulatory mechanism of how breast cancer cells have acquired higher IR/IGF1R ratio.
Abstract 6210: Loss of inflammation-related genes and inflammation inhibitors effectively targets ER- breast cancer cell metastasis
Authors: Chaeun (Christine) Song, Val J. Lowe, SeungBaek Lee
Journal: Cancer Research (2022)

Abstract The anti-estrogen tamoxifen is a highly effective hormonal therapy for hormonal (HR+) breast cancer patients. However, the estrogen receptor-negative, progesterone receptor-positive (ER-/PR+) subtype does not receive the benefits of tamoxifen. Therefore ER-/PR+ breast cancer have a poor clinical outcome, but drug development for ER-/PR+ breast cancer is not well studied. Here, we found that gene expression in ER-/PR+ HR+ breast cancer is positively related to triple negative breast cancer (TNBC) and not HR+ breast cancer using 4,319 breast cancer patients database. Especially, inflammation-related genes, A20/TNFAIP3, CDC20 and CASP1/Caspase-1, which are highly expressed in TNBC, are also upregulated in ER-/PR+ HR+ breast cancer. Suppression of A20/TNFAIP3, CDC20 and CASP1 inhibit cancer cell growth and metastasis in ERα KO (ER-/PR+) cell lines. Interestingly, loss of ERα in HR+ cell lines is not responsive to tamoxifen, but highly sensitive to inflammation inhibitor, Ac-YVAD-CHO. In in vitro and ex vivo models, inflammation inhibitor specifically blocks ER-/PR+ tumor proliferation and migration. These findings suggest that the inflammation inhibitor might be the first potential target therapy for ER-/PR+ HR breast cancer patients. Citation Format: Chaeun (Christine) Song, Val J. Lowe, SeungBaek Lee. Loss of inflammation-related genes and inflammation inhibitors effectively targets ER- breast cancer cell metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6210.
Abstract 1547: LncRNA UCA1 modulates glucose metabolism proteins in colorectal cancer
Authors: Sophia Leslie, Kyle Doxtater, Samantha Lopez, Adithya Anilkumar, Meena Jaggi, Subhash Chauhan, Manish Tripathi
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) is the primary cause of cancer-related deaths worldwide. According to the American Cancer Society, it is the third most common cancer diagnosed in adults in the United States. It will have an estimated 149,500 new cases of colon cancer in 2021. In addition, studies show CRC has increased morbidity with obesity and obesity-related diseases such as diabetes. In a geographical area of The Rio Grande Valley which has a high incidence of diabetes, understanding the connection between CRC and diabetes is essential. Our lab identified LncRNA UCA1, a poor prognosis marker in CRC, responsible for increased proliferation and upregulating glucose metabolic pathway. First, we investigated the possible role of UCA1 in glucose metabolism, finding that UCA1 overexpressing cells (SW480+UCA1) showed a higher glucose consumption than their vector. The inverse of this trend was established when we knockdown UCA1 (SW620+shUCA1). Further, we found that overexpressing UCA1 increases the migration, invasion, and proliferation of SW480 cells. A vital aspect of the metastatic progression is when the cell survives detachment from the extracellular matrix. A route in which they overcome apoptosis is through modulation of the metabolic pathways, upregulating such markers as GLUT1, FDFT1, SGK1, and HIF1α. At 36hrs of anchorage-independent stimulation, we found an uptick in glucose consumption and lactate production and an increase in the expression of GLUT1, FDFT1, SGK1, and HIF1α compared to 0hrs. The Warburg effect is when glycolysis is no longer connected to the tricarboxylic acid cycle or oxidative phosphorylation. The increase in expression of the markers GLUT1, FDFT1, SGK1, and HIF1α indicates aerobic metabolic activity during anchorage-independent growth with UCA1 expression. This relationship needs to be further examined and could lead to understanding the increased morbidity associated with diabetes and CRC. Citation Format: Sophia Leslie, Kyle Doxtater, Samantha Lopez, Adithya Anilkumar, Meena Jaggi, Subhash Chauhan, Manish Tripathi. LncRNA UCA1 modulates glucose metabolism proteins in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1547.
Imaging of Glycosaminoglycans in Ascending Aortic Aneurysms With Chemical Exchange Saturation Transfer MRI
Authors: Rokhsana Mortuza, Justin A. Ching-Johnson, Hao Yin, Caroline O’Neil, Alicia E. Cronin, Varinder K. Randhawa, Zengxuan Nong, Abdulaziz Ahmed Hashi, Alex X. Li, Robert Bartha, Michael W.A. Chu, J. Geoffrey Pickering
Journal: JACC. Cardiovascular imaging (2022)
Abstract 2326: Preclinical characterization of MTB-9655, a first-in-class, clinical stage ACSS2 inhibitor
Authors: Andreas Goutopoulos, Iris Amanati, Ali Fattaey, Avital Hay-Koren, Philippe Nakache, Omri Erez, Dimitri Kovalerchik, Dikla Paz, Simone Botti, Hannah Oppenheimer, Irit Fainer
Journal: Cancer Research (2022)

Abstract ACSS2 is a nucleo-cytoplasmic enzyme that converts acetate into Acetyl-CoA. In many tumor types ACSS2 is dramatically upregulated in response to the hypoxic and lipid-depleted conditions often encountered in the tumor microenvironment. In these conditions, ACSS2 allows tumor cells to switch to acetate as key carbon source to meet their anabolic and energetic needs and thereby they become dependent on both acetate and ACSS2. MTB-9655 is a novel, potent and selective ACSS2 inhibitor discovered at Metabomed. It is currently in Phase I clinical investigation on patients with tumors with high levels of ACSS2. The antitumor effect of MTB-9655 was characterized in a number of PDX models across various tumor types. PDX tumors that exhibit over 50 TPM copies of ACSS2 mRNA showed significant sensitivity to ACSS2 inhibition in vivo. TCGA analyses suggests that most GU tumors, such as hepatocellular, gastric, colorectal show high frequency of ACSS2 upregulation and therefore present an opportunity for treatment with MTB-9655. In addition, PDX studies revealed a significant combination effect with cisplatin and gemcitabine. This opens opportunities for combination treatments of several GU cancers expressing high levels of ACSS2, such as ovarian and breast cancers.As a potential PD biomarker assay, 11C acetate PET imaging was explored preclinically in tumor-bearing mice as a way to assess inhibition of acetate flux in the presence of ACSS2 inhibitor. MTB-9655 resulted in robust inhibition of 11C acetate uptake in tumors in a dose-dependent manner opening the possibility of using 11C acetate PET as a clinical PD biomarker. Citation Format: Andreas Goutopoulos, Iris Amanati, Ali Fattaey, Avital Hay-Koren, Philippe Nakache, Omri Erez, Dimitri Kovalerchik, Dikla Paz, Simone Botti, Hannah Oppenheimer, Irit Fainer. Preclinical characterization of MTB-9655, a first-in-class, clinical stage ACSS2 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2326.
Abstract 3037: RSK4 inhibition promotes pseudo-hypoxic metabolic responses in lung adenocarcinoma
Authors: Lucksamon Thamlikitkul, Peng Chai, Cristina Balcells Nadal, Rajat Roy, Xiao-Ming Sun, Marion MacFarlane, Hector Keun, Michael Seckl, Olivier Pardo
Journal: Cancer Research (2022)

Abstract Background: RSK4 is a member of the p90 Ribosomal S6 kinase family that promotes metastasis and chemoresistance in non-small cell lung cancer and its inhibition improves therapeutic outcome in in vivo and ex vivo models. Here, we show that RSK4 inhibition activates HIF-1alpha and also impacts glucose and glutamine metabolism in lung adenocarcinoma cells. Methods: RSK4 was downregulated in lung adenocarcinoma cells by RNA interference or CRISPR/Cas9 technology. Glycolytic rate assay and mitochondrial stress test were performed using the Seahorse XFe96 analyzer. ATP levels were determined by the CellTiter Glo assay. Intracellular metabolites were profiled by untargeted mass spectrometry and U-13C glutamine labelling. 3D spheroids viability was assessed by CellTiter Glo 3D assay with or without glycolysis inhibition using 2-deoxy-D-glucose (2DG) or glutaminase inhibition using 6-Diazo-5-oxo-L-norleucine (DON). Protein expression was determined by Western blotting. Results: RSK4 downregulation enhanced glycolysis, oxidative phosphorylation, and ATP production in A549 cells. The RSK4-silenced cells showed increased lactate production and glutamine consumption via reductive carboxylation. This sensitized RSK4-silenced cells to 2DG and DON treatments. Mechanistically, RSK4 knockdown upregulates HIF-1alpha in normoxia through decreased activation of PHD2, an enzymes that targets HIF-1alpha for degradation. Stabilization of HIF-1alpha resulted in increased transcription of HK2, the rate limiting enzyme of glycolysis, and GLS1, which hydrolyzes glutamine. Conclusion: RSK4 knockdown promotes a pseudo-hypoxic phenotype in lung adenocarcinoma cells characterized by increased glycolysis and enhanced glutamine utilization via reductive carboxylation. Targeting these changes potentiates the effects of RSK4 inhibition and may represent new therapeutic opportunities for this tumor type. Citation Format: Lucksamon Thamlikitkul, Peng Chai, Cristina Balcells Nadal, Rajat Roy, Xiao-Ming Sun, Marion MacFarlane, Hector Keun, Michael Seckl, Olivier Pardo. RSK4 inhibition promotes pseudo-hypoxic metabolic responses in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3037.
Abstract 6397: Understanding the glioblastoma microenvironment with spatial resolution in PDX models
Authors: Aly O. Abdelkareem, Katalin Osz, Donna Senger, Jennifer A. Chan, Sorana Morrissy
Journal: Cancer Research (2022)

Abstract Glioblastoma multiforme (GBM) is the most common adult brain tumour, and despite aggressive treatment, it recurs fatally. GBM tumours include diverse populations of malignant and non-neoplastic cells with distinct molecular capabilities and with differential levels of sensitivity to treatment. Understanding the cell dynamics that occur during the development of GBM resistance to therapy could reveal key aspects of this process, including how resistance is acquired in time and how the diverse cell types of the tumour microenvironment (TME) contribute to this phenotype. In addition to the role of the TME, GBM exhibits significant tumour heterogeneity with diverse genetic clones coexisting in the same tumor, as well as cells with similar genetic backgrounds capable of adopting distinct transcriptional states and subtypes. The complex and dynamic interactions between tumor and TME remain to be fully studied. This work focuses on the in vivo spatial organization in GBM during disease progression. We generated spatial transcriptomic data from a set of adult GBM samples grown as patient-derived xenograft (PDX) models, profiled at different time points of the disease. Three PDX lines from one GBM patient (derived from tumor core, vascularized area, and infiltrating front) were used to recapitulate the genetic and phenotypic heterogeneity observed in the human disease. Two replicates from each of 8 PDX mice were collected from early, mid, and late time points of tumour growth and data was generated using the 10X Genomics Visium platform. We developed a robust computational pipeline capable of distinguishing admixture of human (tumour) and mouse cells (TME), using state-of-the-art tools. Human and mouse cell types and states were identified using pooled and separate single-cell references of human GBM states, and mouse brain cells from both normal and tumour conditions. With this approach we observe spatially distinct patterns of both (a) tumour infiltration patterns specific to the each PDX line that includes non-random distribution of GBM transcriptional states and genetic clones, and (b) spatially distinct infiltration of TME components including microglial and macrophage populations. Overall, our approach addresses the challenge of understanding the tumor-TME relationship by application of spatial profiling in PDX models, and provides a computational pipeline complex multi-species analysis in the spatial transcriptomic field. Citation Format: Aly O. Abdelkareem, Katalin Osz, Donna Senger, Jennifer A. Chan, Sorana Morrissy. Understanding the glioblastoma microenvironment with spatial resolution in PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6397.
Abstract 583: Improving anti-tumor response by increasing mitochondrial respiration of T-cell
Authors: Meng-Han Wu, Emily Giddlings, Catherine Danis, Megan McCalab, Mark Eric Kohler, Mercedes Rincon
Journal: Cancer Research (2022)

Abstract Chimeric antigen receptor (CAR)-T cell therapy is revolutionary as a promising approach of cancer immunotherapy against lymphoblastic leukemia and lymphoma. While initially effective in up to 90% of patients with B-cell lymphoblastic leukemia, over 40% of patients will relapse, with sub-optimal persistence of functional CAR-T cells underlying many of these relapses. The major challenges of CAR-T cell to effectively eliminate cancer cells are extending persistence of CAR-T cells and retaining the effector function of CAR-T cells in vivo after prolonged in vitro expansion. To overcome such limitations, enhancing mitochondrial metabolism is emerging as an appealing approach to regulate CAR-T cell function, however, increasing mitochondrial respiration and ATP production is a challenging strategy. We have previously identified MCJ/DnaJC15 as an endogenous negative regulator of Complex I of electron transport chain. The absence of MCJ in CD8 cells (MCJ KO CD8 cells) increases Complex I activity, mitochondrial membrane potential, and mitochondrial respiration without affecting glycolysis. Lack of MCJ enhances cytokine secretion and cytotoxicity (two processes dependent on mitochondrial ATP) in CD8 cells in vitro and in vivo. Using the B16 melanoma cell model, we have shown that antigen-specific MCJ KO CD8 cells are superior in killing melanoma cells in vitro and in vivo. We have generated WT and MCJ KO CD19-41BB CAR-T cells and tested their anti-tumor activity against B-cell leukemia. The results reveal that MCJ-deficient CAR-T cells exhibit superior killing capacity against leukemia B cells and prolong survival of the leukemia-bearing mice. Together, these data demonstrate MCJ as an attractive target to enhance CAR-T cell therapy efficacy. Citation Format: Meng-Han Wu, Emily Giddlings, Catherine Danis, Megan McCalab, Mark Eric Kohler, Mercedes Rincon. Improving anti-tumor response by increasing mitochondrial respiration of T-cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 583.
Abstract 1863: Mouse strain variations in drug-induced lung stromal responses
Authors: Carlos M. Leon, Zheng Gong, Qing Li, Jiayuan Shi, Wulin Zuo, Muneer G. Hasham, Lenny Shultz, Sheng Li, Guangwen Ren
Journal: Cancer Research (2022)

Abstract Chemotherapy has significantly improved the survival of cancer patients. However, the vast variation in treatment responses remains a major issue in the clinic. It is imperative to understand the molecular mechanisms underlying treatment failure in specific populations of patients. Genetic diversity has been recognized to mainly account for the differences in drug responses among patients. Yet, it is not feasible to map the responsible genetic variants within millions of single-nucleotide polymorphisms in the human genome in clinical settings with a limited number of subjects and insufficient genomic information. Genetically diverse mice are an ideal tool to overcome the limitations in clinical studies and model drug responses in hosts that require genetic susceptibility and resistance factors. Recent studies have also implicated a critical role for host cells (i.e., the tissue microenvironment) in building a protective “niche” for tumor cells enabling their escape from chemotherapeutic treatments. Notably, the host regenerative response upon chemotherapy “injury,” which is regarded as an intrinsic host mechanism to repair damaged tissues, may be exploited by tumor cells for their local recurrence or distant metastases. In this study, using a lung injury model, we determined how drug-induced lung stromal wound healing responses differed among eight inbred mouse strains (BALB/cJ, NSG, C57BL/6J, CH3/HeJ, CBA/J, SJL/J, A/J, and NOD/ShiLtJ). Upon either cisplatin or doxorubicin stimulation, the wound healing-associated genes Il-6, Spp1, Cxcl1, and Ccl2 were all found upregulated in lung stromal cells but showed a great variation across different strains. Furthermore, we performed single-cell RNA sequencing on the lung stromal cells and immune cells isolated from three selected mouse strains (BALB/cJ, C57BL/6J, and NOD/ShiLtJ) without and with doxorubicin treatment in vivo. The transcriptomic analyses revealed strain-specific and non-specific therapy-elicited gene signatures in different types of lung tissue cells. Collectively, our results signify an association between genetic backgrounds and drug-induced host responses in mice. The next steps of the study aim to understand how genetic diversity would functionally impact drug-induced lung tissue regeneration, lung inflammation, and post-therapy tumor relapse or metastasis in the lung. Citation Format: Carlos M. Leon, Zheng Gong, Qing Li, Jiayuan Shi, Wulin Zuo, Muneer G. Hasham, Lenny Shultz, Sheng Li, Guangwen Ren. Mouse strain variations in drug-induced lung stromal responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1863.
Abstract 5395: DNA damage repair gene mutations predict the efficacy of platinum-based chemotherapy in colorectal cancer
Authors: Yan Lin, Jinyan Zhang, Xiaoli Liao, Yumei Zhang, Min Luo, Qian Li, Mingzhi Xie, Chaoyong Liang, Sina Liao, Yating Zheng, Xue Hu, Mengli Huang, Rong Liang, Yongqiang Li
Journal: Cancer Research (2022)

Abstract Background: DNA damage repair (DDR) mutations are known to predict response to platinum-based chemotherapy in multiple solid tumors. However, their predictive value remained unknown in patients with colorectal cancer. Methods: The genomic and survival datas from the TCGA-COAD and TCGA-READ cohorts of patients receiving platinum-based chemotherapy were used to analyze the predictive value of DDR mutations on platinum-based chemotherapy. Result: The DDR genes were commonly mutated (85.82%) in the TCGA-COAD and TCGA-READ cohorts. The objective response rates (ORRs) were 80% for the patients with DDR mutations (DDRmut) subgroup and 56% for the DDR wild-type (DDRwt) subgroup (P&amp;lt;0.05), and the disease control rates (DCRs) were 86% for the DDRmut subgroup and 56% for the DDRwt subgroup (P&amp;lt;0.05). In patients with stage I, II and III colorectal cancer, there was no significant difference in the overall survival (OS) between DDRmut subgroup and DDRwt subgroup (Hazard Ratio=0.48, 95%CI 0.1−2.31, log-rank P=0.35). In patients with stage IV colorectal cancer, the OS was significantly better among the DDRmut patients than in the DDRwt subgroup (Hazard Ratio=0.21, 95%CI 0.06−0.8, P= 0.011). Conclusions: DDR mutations may serve as a positive predictor of platinum-based chemotherapy therapy in patients with CRC and their clinical value warrants further investigation. Citation Format: Yan Lin, Jinyan Zhang, Xiaoli Liao, Yumei Zhang, Min Luo, Qian Li, Mingzhi Xie, Chaoyong Liang, Sina Liao, Yating Zheng, Xue Hu, Mengli Huang, Rong Liang, Yongqiang Li. DNA damage repair gene mutations predict the efficacy of platinum-based chemotherapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5395.